EE was developed in the 1930s and was introduced for medical use in 1943,[11][12] the drug started being used in birth control pills in the 1960s.[13] Today, EE is found in almost all combined forms of birth control pills and is nearly the exclusive estrogen used for this purpose, making it one of if not the most widely used estrogens.[14][15]

There are many uses for EE, it is most commonly used as contraception in combined oral contraceptives (COC), also known as birth control, to prevent pregnancy after sex. EE in its birth control formulation is not only used to prevent pregnancy, but can also be used to treat absence of menstruation, symptoms during mensturation, and acne, the amount of EE in COCs has reduced over the years.[medical citation needed]

EE is also used as menopausal hormone therapy, the main reason for using HRT in menopausal women is to relieve common vasomotor symptoms such as hot flashes, night sweats, and flushing. Studies have found that estrogen replacement helps improve these symptoms when compared to a placebo.[16] Other common menopause symptoms such as vaginal dryness (which can cause pain during sexual intercourse), vaginal itching, and depressed mood, can benefit from HRT; in addition to treatment of menopausal symptoms, EE has been used as a component of feminizing hormone therapy for transgender women.[17] However, it is no longer commonly used nor recommended for this purpose, with estradiol having largely superseded it.[17]

EE or any estrogen alone is contraindicated for women who have a uterus due to the increased risk of endometrial cancer; giving a progestin with an estrogen mitigates the risk.[18]

EE should be avoided in women with current breast cancer due to a possible worsening of prognosis.[20]

EE should also be avoided in breastfeeding women who are less than 21 days postpartum due to an increased risk of VTE.[21] EE use in breastfeeding women who are at least 21 days postpartum should be discussed with a provider and include information on the advantages, disadvantages, and alternatives for using EE.[21]

EE carries a greater risk of blood clot formation and VTE than does natural estradiol, which is thought to be due to different degrees of hepatic metabolism between the two drugs (see below).

The original formulations of COCs contained as much as 150 μg EE.[25] However, it was soon found that EE is associated with incidence of VTE and that the risk is dose-dependent.[25] Subsequently, the dosage of EE was greatly reduced, and is now generally between 25 and 35 μg,[25] in some cases less than 20 μg,[25] and not more than 50 μg.[26][27][24] These lower dosages have a significantly reduced risk of VTE with no loss of contraceptive effectiveness.[25] However, discontinuation of OCs are common with doses of estrogen from 10 to 20 μg due to its association "with higher rates of bleeding pattern disruptions."[23] According to a bulletin posted by the U.S.FDA, the rate of deep vein thrombosis in women taking COCs containing 20 to 40 μg EE is 4 per 10,000, which is approximately equivalent to the rate of 3 per 10,000 in women not taking a COC.[28] No study has shown a further reduced risk of VTE below an EE dosage of 30 or 35 μg.[25]

The high doses of EE that were used in early COCs were associated with a significantly increased risk of endometrial cancer in certain preparations, for instance those containing the progestogen dimethisterone.[32] Unopposed estrogens like EE have carcinogenic effects in the endometrium and progestogens protect against these effects, but dimethisterone is a relatively weak progestogen and was unable to adequately antagonize the endometrial carcinogenic effects of EE, in turn resulting in the increased risk of endometrial cancer.[32] COCs containing dimethisterone have since been discontinued (with more potent progestogens used instead) and doses of EE in COCs in general have been dramatically reduced, abrogating the risk;[32] in turn, most studies of modern COCs have found a decreased risk of endometrial cancer.[33]

Paracetamol (acetaminophen) has been found to competitively inhibit the sulfation of EE, with pretreatment of 1,000 mg of paracetamol significantly increasing the AUC levels of EE (by 22%) and decreasing the AUC levels of EE sulfate in women.[22] The same has been found for ascorbic acid (vitamin C) and EE, although the significance of the interaction has been regarded as dubious.[22]

In contrast to estradiol, it is unlikely that there is a pharmacokinetic interaction between smoking (which potently induces certain cytochrome P450enzymes and markedly increases the 2-hydroxylation of estradiol) and EE.[22] This suggests that estradiol and EE are metabolized by different cytochrome P450 enzymes.[22] There is, however, an increased risk of cardiovascular complications with smoking and EE, similarly to the case of smoking and other estrogens.[22]

The 19-nortestosterone progestins, gestodene and, to a lesser extent, desogestrel, have been found to inhibit cytochrome P450 enzymes and to progressively inhibit the metabolism and increase the concentrations of EE.[22]

EE has been found to significantly increase (by 38%) the AUC of omeprazole (which is metabolized by CYP2C19).[22]

Orally, EE is about 100 times as potent by weight as natural estrogens like micronized estradiol and conjugated estrogens, which is largely due to substantially greater resistance to first-pass metabolism.[44][45][46] In contrast, the potencies of EE and natural estrogens are similar when they are administered intravenously, due to the bypassing of first-pass metabolism.[25] Relative to its prodrugmestranol, EE is about 1.7 times as potent by weight orally.[45]

Birth control pills containing EE have been found to increase circulating SHBG levels by 2- to 4-fold in women and to reduce free testosterone concentrations by 40 to 80%.[54] Birth control pills containing high doses of EE can increase SHBG levels in women by as much as 5- to 10-fold,[57] this is similar to the 5- to 10-fold increase in SHBG levels that occurs during pregnancy.[57] Due to the marked increase in SHBG levels, free testosterone levels become very low during treatment with EE-containing birth control pills;[8] in men, a study found that treatment with a relatively low dosage of 20 μg/day EE for five weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease in free testosterone levels, increased total circulating levels of testosterone by 50% (via upregulation of gonadal testosterone production due to reduced negative feedback by androgens on the hypothalamic–pituitary–gonadal axis).[53] The stimulation of hepatic SHBG production by EE is far stronger than with other estrogens like estradiol, owing to the high resistance of EE to inactivation in the liver and hence its disproportionate effects in this part of the body.[58][8][59]

Estrogens are antigonadotropins and are able to suppress the secretion of LH from the pituitary gland and by extension gonadal testosterone production.[60][61]High-dose estrogen therapy, including with EE, is able to suppress testosterone levels in men by around 95%, or into the castrate/female range.[62][60][61]

As can be seen in the tables, EE shows strong and disproportionate effects on hepatic protein production relative to estradiol,[10] the liver as well as the uterus express 17β-hydroxysteroid dehydrogenase (17β-HSD), and this enzyme serves to inactivate estradiol and effectively suppress its potency in these tissues (analogously but in the opposite manner to potentiation of testosterone by 5α-reductase into the more potent dihydrotestosterone in so-called androgenic tissues like the skin, hair follicles, and prostate gland)[64] by reversibly converting it into the far less potent estrogen estrone (which has approximately 4% of the estrogenic activity of estradiol, most of which is actually due to conversion into estradiol).[10] In contrast to estradiol, the 17α-ethynyl group of EE prevents oxidation of the C17β position of EE by 17β-HSD, and for this reason, EE is not inactivated in these tissues and has much stronger relative estrogenic activity in them.[10][65][9] This is the mechanism of the disproportionately strong effects of EE on hepatic protein production,[10][65] which results in a greatly increased magnitude of effect on VTE risk relative to estradiol.[66]

On the other hand, due to the loss of inactivation of EE by 17β-HSD in the endometrium (uterus), EE is relatively more active than estradiol in the endometrium and, for this reason, is associated with a significantly lower incidence of vaginal bleeding and spotting in comparison,[10] this is particularly so in the case of combined estrogen and progestogen therapy (as in COCs or menopausal HRT), as progestogens induce the expression of 17β-HSD in the endometrium.[10] The reduced vaginal bleeding and spotting with EE is one of the main reasons that it is used in COCs instead of estradiol,[4] in spite of its potentially inferior safety profile (related to its adverse effects on hepatic protein synthesis and VTE incidence).[67]

EE has been found to have similar effects on hepatic protein production and VTE risk regardless of whether the route of administration is oral, transdermal, or vaginal, indicating that oral versus non-oral routes do not reduce the hepatic actions of EE relative to non-hepatic actions;[65] in contrast, at typical menopausal dosages, oral estradiol shows significant effects on hepatic protein production whereas transdermal estradiol shows few or no such effects.[10]

HF = clinical relief of hot flashes; FSH = suppression of FSH levels; HDL-C, SHBG, CBG, and AGT = increase in the serum levels of these hepatic proteins. Bioidentical = identical to those found in humans. Natural = naturally occurring but not identical to those found in humans (e.g., estrogens of other species). Synthetic = man-made, does not naturally occur in animals or in the environment.

The oralbioavailability of EE is 45% on average, with a wide range of 20% to 74% (though most commonly between 38 and 48%) that is due to high interindividual variability.[8][5] Although relatively low, the oral bioavailability of EE is considerably higher than that of micronized estradiol (5%).[3][8] Following a single 20 μg dose of EE in combination with 1 mg norethisterone in postmenopausal women, EE concentrations have been found to reach a maximum of 50 pg/mL within an average of 1.5 hours.[10] Following the first dose, mean levels of EE in general further increase by about 50% until steady-state concentrations are reached;[10] steady-state is reached after one week of daily administration.[35] For comparison, the mean peak levels of estradiol achieved with 2 mg micronized estradiol or estradiol valerate are 40 pg/mL following the first dose and 80 pg/mL after three weeks of administration.[10] These concentrations of estradiol are in the same range as the concentrations of EE that are produced by an oral dose of EE that is 100 times lower by weight, which is in accordance with the approximately 100-fold increased oral potency of EE relative to estradiol;[44][10] in accordance with the high interindividual variability in the oral bioavailability of EE, there is a large degree of interindividual variation in EE levels.[10]

Unlike estradiol, which binds with high affinity to SHBG, EE has very low affinity for this protein of about 2% of that of estradiol, and hence does not bind to it importantly.[51] Instead, EE is bound almost exclusively to albumin (97–98%).[6][10][8][68] As estradiol that is bound to SHBG is considered to be hormonally inactive,[69] the lack of binding of EE to SHBG may in part be involved in its increased comparative potency.[citation needed]

Due to high first-pass metabolism in the intestines and liver, only 1% of an oral dose of an EE appears in the circulation as EE itself,[10] during first-pass metabolism, EE is extensively conjugated via sulfation into the hormonally inert EE sulfate, and levels of EE sulfate in circulation are between 6- and 22-fold higher than those of EE.[10] For comparison, with oral administration of 2 mg micronized estradiol, levels of estrone and estrone sulfate are 4- to 6-fold and 200-fold higher than those of estradiol, respectively.[10] In contrast to estradiol, EE, due to steric hindrance by its C17α ethynyl group, is not metabolized or inactivated by 17β-HSD,[9] and this is the primary factor responsible for the dramatically increased potency of oral EE relative to oral estradiol.[10] Due to the formation of EE sulfate, enterohepatic circulation is involved in the pharmacokinetics of EE similarly to estradiol, although to a lesser extent.[10]

Aside from sulfate conjugation, EE is mainly metabolized by hydroxylation into catechol estrogens,[10] this is mainly by 2-hydroxylation into 2-hydroxy-EE, which is catalyzed primarily by CYP3A4.[8] Hydroxylation of EE at the C4, C6α, and C16β positions into 4-, 6α-, and 16β-hydroxy-EE has also been reported, but appears to contribute to its metabolism to only a small extent.[8] 2- and 4-methoxy-EE are also formed via transformation by catechol O-methyltransferase of 2- and 4-hydroxy-EE.[10] Unlike the case of estradiol, 16α-hydroxylation does not occur with EE, owing to steric hindrance by its ethynyl group at C17α,[8][10] the ethynylation of EE is largely irreversible, and so EE is not metabolized into estradiol, unlike estradiol esters.[10] A review found that the range of the reported terminal half-life of EE in the literature was 13.1 to 27.0 hours.[3] Another review reported a terminal half-life of EE of 10–20 hours.[8] However, the terminal half-life of EE has also been reported by other sources to be as short as 7 hours[9] and as long as 36 hours.[2]

Unlike the case of estradiol, in which there is a rapid rise in its levels and which remain elevated in a plateau-like curve for many hours, levels of EE fall rapidly after peaking,[10] this is thought to be because estrone and estrone sulfate can be reversibly converted back into estradiol and serve as a hormonally inert reservoir for estradiol, whereas the EE sulfate reservoir for EE is much smaller in comparison.[10]

EE, following oxidative formation of a very reactive metabolite, irreversibly inhibitscytochrome P450enzymes involved in its metabolism, and this may also play a role in the increased potency of EE relative to estradiol.[10] Indeed, EE is said to have a marked effect on hepatic metabolism, and this is one of the reasons, among others, that natural estrogens like estradiol may be preferable.[68]

EE was the first orally active synthetic estrogen and was described in 1938 by Hans Herloff Inhoffen and Walter Hohlweg of Schering AG in Berlin.[71][72][73][74][75] It was approved by the FDA in the U.S. on June 25, 1943 and marketed by Schering under the brand name Estinyl.[12] The FDA withdrew approval of Estinyl effective June 4, 2004 at the request of Schering, which had discontinued marketing it.[76]

EE was first used in COCs, as an alternative to mestranol, in 1964, and shortly thereafter superseded mestranol in COCs.[13]

Ethinylestradiol is the Englishgeneric name of the drug and its INN, USAN, BAN, and JAN.[77][1][78][70] It has also been spelled as ethynylestradiol, ethynyloestradiol, and ethinyloestradiol (all having the same pronunciation), and the latter was formerly its BAN but was eventually changed.[77][1][70] In addition, a space is often included in the name of EE such that it is written as ethinyl estradiol (as well as variations thereof), and this is its USP name.[77][70] The generic name of EE in French and its DCF are éthinylestradiol, in Spanish is etinilestradiol, in Italian and its DCIT are etinilestradiolo, and in Latin is ethinylestradiolum.[77][70]

EE has been marketed as a standalone oral drug under the brand names Esteed, Estinyl, Feminone, Lynoral, Menolyn, Novestrol, Palonyl, Spanestrin, and Ylestrol among others, although most or all of these formulations are now discontinued.[79][80][70] It is marketed under a very large number of brand names throughout the world in combination with progestins for use as an oral contraceptive;[77] in addition, EE is marketed in the U.S. in combination with norelgestromin under the brand names Ortho Evra and Xulane as a contraceptive patch, in combination with etonogestrel under the brand name NuvaRing as a contraceptive vaginal ring, and in combination with norethisterone acetate under the brand name FemHRT in oral hormone replacement therapy for the treatment of menopausal symptoms.[81]

^ abcdShellenberger, T. E. (1986). "Pharmacology of estrogens". The Climacteric in Perspective: 393–410. doi:10.1007/978-94-009-4145-8_36. Ethinyl estradiol is a synthetic and comparatively potent estrogen. As a result of the alkylation in 17-C position it is not a substrate for 17β dehydrogenase, an enzyme which transforms natural estradiol-17β to the less potent estrone in target organs.

^Committee on the Relationship Between Oral Contraceptives and BreastCancer (1 January 1991). Oral Contraceptives and Breast Cancer. National Academies. pp. 143–. NAP:13774. Following a recommendation by its Fertility and Maternal Health Drugs Advisory Committee, the Food and Drug Administration (FDA) recently ordered the removal from the market of all oral contraceptives with [ethinylestradiol] contents greater than 50 μg.

^Nathaniel McConaghy (21 November 2013). Sexual Behavior: Problems and Management. Springer Science & Business Media. pp. 177–. ISBN978-1-4899-1133-9. Meyer et al. found that ethinyl estradiol was 75 to 100 times more potent than conjugated estrogen on the basis of the doses required to lower testosterone to the adult female range, 0.1 mg of the former and 7.5 to 10 mg of the latter being necessary.

1.
Drug nomenclature
–
Drug nomenclature is the systematic naming of drugs, especially pharmaceutical drugs. Generic names for drugs are nowadays constructed out of affixes and stems that classify the drugs into different categories, a marketed drug might also have a company code or compound code. The chemical names are the names, based on the molecular structure of the drug. There are various systems of nomenclature and thus various chemical names for any one substance. The most important is the IUPAC name, chemical names are typically very long and too complex to be commonly used in referring to a drug. Sometimes, a company that is developing a drug might give the drug a company code, for example, CDP870 is UCB’s company code for Cimzia. Many of these codes, although not all, have prefixes that correspond to the company name, during development, the company will apply for regulatory approval of the drug by the relevant national regulatory agency, and it will apply for a generic name for that country. It will also apply for an International Nonproprietary Name through the World Health Organization, nowadays the national nonproprietary names are usually the same as the INN. The generic names usually indicate via their stems what drug class the drug belongs to, for example, one can tell that aciclovir is an antiviral drug because its name ends in the -vir suffix. Otherwise the 2 names are both given, joined by hyphens or slashes. For example, suspensions combining trimethoprim and sulfamethoxazole are called either trimethoprim/sulfamethoxazole or co-trimoxazole, similarly, co-codamol is codeine-acetaminophen, and co-triamterzide is triamterene-hydrochlorothiazide. The USP ceased maintaining PENs, but the similar co-prefixed BANs are still current, for drugs that make it all the way through development, testing, and regulatory acceptance, the pharmaceutical company then gives the drug a trade name. The term trade name is a term in the pharmaceutical industry for a brand name or trademark name. For example, Lipitor is Pfizers trade name for atorvastatin, a cholesterol-lowering medication, Drug names are often subject to legal regulation, including approval for new drugs and on packaging to establish clear rules about adulterants and fraudulent or misleading labelling. A national formulary is often designated to define drug names for regulatory purposes, unbiased mentions of a drug place the nonproprietary name first and follow it with the trade name in parentheses, if relevant. This pattern is important for the literature, where conflict of interest is disclosed or avoided. The authors reporting on a study are not endorsing any particular brand of drug and they will often state which brand was used, for methodologic validity, but they do so in a way that makes clear the absence of endorsement. For example, the 2015 American Society of Hematology publication policies say, Non-proprietary names should be used and he first letter of the name of a proprietary drug should be capitalized

2.
Drugs.com
–
Drugs. com is an online pharmaceutical encyclopedia which provides drug information for consumers and healthcare professionals primarily in the USA. The domain Drugs. com was registered by Bonnie Neubeck in 1994. In 1999 at the height of the boom, Eric MacIver purchased an option to buy the domain from Neubeck. com. Venture Frogs sold the drugs. com domain name to an investor in June 2001. The Drugs. com website is owned and operated by the Drugsite Trust, the Drugsite Trust is a privately held Trust administered by two New Zealand pharmacists, Karen Ann and Phillip James Thornton The Drugs. com website was officially launched in September 2001. Stedmans, AHFS, Harvard Health Publications, Mayoclinic, North American Compendiums, in March 2008, Drugs. com announced the release of Mednotes —an online personal medication record application which connected to Google Health. In May 2010, U. S. FDA announced a collaboration with Drugs. com to distribute consumer health updates on the Drugs. com website, Drugs. com is certified by the TRUSTe online privacy certification program and the HONcode Health on the Net Foundation

3.
Regulation of therapeutic goods
–
The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the level, or at both state and national levels by various bodies, as is the case in Australia. The role of therapeutic goods regulation is designed mainly to protect the health, regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed, there is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration, there are 5 main categories, Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies and some large supermarkets, red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti allergenics, Anti inflammatories, and other medicines, in Brazil, governmental control is loose on this type, it is not uncommon to buy this type of prescription medicine over the counter without a prescription. Red Stripe Psychoactive Medicines - These medicines are only with a Special Control white medical prescription with carbon copy. The original must be retained by the pharmacist after the sale, Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category, black Stripe Medicines - These medicines are sold only with the Blue B Form medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives, some anorexic inducers and other habit-inducing controlled medicines, includes amphetamines and other stimulants, opioids and other strong habit-forming controlled medicines. In Canada, regulation of goods are governed by the Food and Drug Act. In addition, the Controlled Drugs and Substances Act requires additional regulatory requirements for controlled drugs, the regulation of drugs in Burma is governed by the Food and Drug Administration and Food and Drug Board of Authority. The regulation of drugs in China is governed by the China Food, Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency. The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product, Medicines in the Republic of Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs are divided into five categories based on their potential for misuse, cD1, cannabis, lysergamide, coca leaf, etc. Use prohibited except in limited circumstances where a license has been granted, CD2, amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc

4.
European Medicines Agency
–
The European Medicines Agency is a European Union agency for the evaluation of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products, roughly parallel to the drug part of the U. S. The EU is currently the source of about one-third of the new drugs brought onto the market each year. After the United Kingdom withdrawal from the European Union referendum the agency is preparing to relocate, more specifically, it coordinates the evaluation and monitoring of centrally authorised products and national referrals, developing technical guidance and providing scientific advice to sponsors. Its scope of operations is medicinal products for human and veterinary use including biologics and advanced therapies, the agency is composed of the Secretariat, a management board, seven scientific committees and a number of scientific working parties. The Management Board provides administrative oversight to the Agency, including approval of budgets and plans, the Agency decentralises its scientific assessment of medicines by working through a network of about 4500 experts throughout the EU. The EMA draws on resources of over 40 National Competent Authorities of EU Member states, the centralised procedure is also open to products that bring a significant therapeutic, scientific or technical innovation, or is in any other respect in the interest of patient or animal health. As a result, the majority of genuinely novel medicines are authorised through the EMA, for products eligible for or requiring centralised approval, a company submits an application for a marketing authorisation to the EMA. A single evaluation is carried out through the Committee for Medicinal Products for Human Use, if the Committee concludes that the quality, safety and efficacy of the medicinal product is sufficiently proven, it adopts a positive opinion. This is sent to the European Commission to be transformed into a marketing authorisation valid for the whole of the EU, a special type of approval is the paediatric-use marketing authorisation, which can be granted for medical products intended exclusively for paediatric use. The CHMP is obliged by the regulation to reach decisions within 210 days and this compares well with the average of 500 days taken by the U. S. Food and Drug Administration. The Committee for Medicinal Products for Veterinary Use operates in analogy to the CHMP as described above, the Committee on Orphan Medicinal Products administers the granting of orphan drug status since 2000. The COMP evaluates the application and makes a recommendation for the designation which is granted by the European Commission. The Paediatric Committee deals with the implementation of the legislation in Europe Regulation No 1901/2006 since 2007. It assesses the quality, safety and efficacy of ATMPs, a seventh committee, the Pharmacovigilance Risk Assessment Committee has come into function in 2012 with the implementation of the new EU pharmacovigilance legislation. Referrals The Agency coordinates arbitration procedures relating to medicinal products that are approved or under consideration by Member States in non-centralized authorisation procedures, telematics projects The Agency is responsible for implementing a central set of pan-European systems and databases such as EudraVigilance, EudraCT and EudraPharm. Following the decision of the United Kingdom to vote to leave the European Union, according to EU Law the European Commission will need to decide the criteria surrounding the fate of the EMAs location. The heads of state will then meet to vote on their preferred successor, the EUs Health Commissioner Vytenis Andriukaitis has said in the past that the preferred choice would be a location where an easy set up and guarantee of smooth operations would be available

5.
United States
–
Forty-eight of the fifty states and the federal district are contiguous and located in North America between Canada and Mexico. The state of Alaska is in the northwest corner of North America, bordered by Canada to the east, the state of Hawaii is an archipelago in the mid-Pacific Ocean. The U. S. territories are scattered about the Pacific Ocean, the geography, climate and wildlife of the country are extremely diverse. At 3.8 million square miles and with over 324 million people, the United States is the worlds third- or fourth-largest country by area, third-largest by land area. It is one of the worlds most ethnically diverse and multicultural nations, paleo-Indians migrated from Asia to the North American mainland at least 15,000 years ago. European colonization began in the 16th century, the United States emerged from 13 British colonies along the East Coast. Numerous disputes between Great Britain and the following the Seven Years War led to the American Revolution. On July 4,1776, during the course of the American Revolutionary War, the war ended in 1783 with recognition of the independence of the United States by Great Britain, representing the first successful war of independence against a European power. The current constitution was adopted in 1788, after the Articles of Confederation, the first ten amendments, collectively named the Bill of Rights, were ratified in 1791 and designed to guarantee many fundamental civil liberties. During the second half of the 19th century, the American Civil War led to the end of slavery in the country. By the end of century, the United States extended into the Pacific Ocean. The Spanish–American War and World War I confirmed the status as a global military power. The end of the Cold War and the dissolution of the Soviet Union in 1991 left the United States as the sole superpower. The U. S. is a member of the United Nations, World Bank, International Monetary Fund, Organization of American States. The United States is a developed country, with the worlds largest economy by nominal GDP. It ranks highly in several measures of performance, including average wage, human development, per capita GDP. While the U. S. economy is considered post-industrial, characterized by the dominance of services and knowledge economy, the United States is a prominent political and cultural force internationally, and a leader in scientific research and technological innovations. In 1507, the German cartographer Martin Waldseemüller produced a map on which he named the lands of the Western Hemisphere America after the Italian explorer and cartographer Amerigo Vespucci

6.
Tablet (pharmacy)
–
A tablet is a pharmaceutical dosage form. Tablets may be defined as the solid unit dosage form of medicament or medicaments with or without suitable excipients and it comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose. The compressed tablet is the most popular form in use today. About two-thirds of all prescriptions are dispensed as solid dosage forms, a tablet can be formulated to deliver an accurate dosage to a specific site, it is usually taken orally, but can be administered sublingually, buccally, rectally or intravaginally. The tablet is just one of the forms that an oral drug can take such as syrups, elixirs, suspensions. Medicinal tablets were made in the shape of a disk of whatever color their components determined. Tablets are often stamped with symbols, letters, and numbers, sizes of tablets to be swallowed range from a few millimeters to about a centimeter. Pills are thought to date back to around 1500 BC, earlier medical recipes, such as those from 4000 BC, were for liquid preparations rather than solids. The first references to pills were found on papyruses in ancient Egypt, medicinal ingredients, such as plant powders or spices, were mixed in and formed by hand to make little balls, or pills. In ancient Greece, such medicines were known as katapotia, and the Roman scholar Pliny, Pills have always been difficult to swallow and efforts long have been made to make them go down easier. In medieval times, people coated pills with slippery plant substances, another approach, used as recently as the 19th century, was to gild them in gold and silver, although this often meant that they would pass through the digestive tract with no effect. In the 1800s sugar-coating and gelatin-coating was invented, as were gelatin capsules, in 1843, the British painter and inventor William Brockedon was granted a patent for a machine capable of Shaping Pills, Lozenges and Black Lead by Pressure in Dies. The device was capable of compressing powder into a tablet without use of an adhesive, today, pills include tablets, capsules, and variants thereof like caplets—essentially anything with medication that can be digested, minus the liquid forms, colloquially falls into the pill category. A caplet is a smooth, coated, oval-shaped medicinal tablet in the shape of a capsule. Many caplets have a running down the middle so they may be split in half easier. An orally disintegrating tablet or orodispersible tablet, is a dosage form available for a limited range of over-the-counter. In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, content uniformity ensures that the same API dose is delivered with each tablet. Some APIs may be tableted as pure substances, but this is rarely the case, normally, a pharmacologically inactive ingredient termed a binder is added to help hold the tablet together and give it strength

7.
Contraceptive patch
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A contraceptive patch, also known as the patch, is a transdermal patch applied to the skin that releases synthetic estrogen and progestin hormones to prevent pregnancy. They have been shown to be as effective as the oral contraceptive pill with perfect use. The only currently available contraceptive patches are Xulane in the United States, the patches are packaged in boxes of three and are only available by prescription. A woman applies her first patch onto her upper arm, buttocks, abdomen or thigh on either the first day of her menstrual cycle or on the first Sunday following that day. The day of application is known from that point as patch change day, seven days later, when patch change day comes again, the woman removes the patch and applies another to one of the approved locations on the body. This process is repeated again on the next patch change day, on the following patch change day, the patch is removed and not replaced. The woman waits 7 days without a patch in place, extended use regimens, where patches are used for several weeks before a patch-free week, have been studied. The patch should be applied to skin that is clean, dry and this means, if skin is red, irritated, or cut, the patch should not be placed in that area. Additionally, avoid using lotions, powder, or makeup around the area where the patch is, in the case that a woman wishes to begin using the contraceptive patch following a first trimester abortion or miscarriage, patch application can be done immediately afterwards. This can be considered the same as a day 1 start above, like all combined hormonal contraceptives, Ortho Evra / Evra works primarily by preventing ovulation. A secondary mechanism of action is inhibition of sperm penetration by changes in the cervical mucus, the 20 cm² Ortho Evra contraceptive patch contains 750 µg ethinylestradiol and 6000 µg norelgestromin. The 20 cm² Evra contraceptive patch contains 600 µg ethinylestradiol and 6000 µg norelgestromin, because the Ortho Evra patch works similar to that of birth control pills, many of the benefits are the same. For example, the patch may make a womans period lighter and it may also help to clear acne, decrease cramps, and reduce PMS symptoms. Additionally, the patch is associated with a protection against iron deficiency anemia, ovarian cysts, pelvic inflammatory disease. The patch is a simple and convenient form of control that only requires weekly attention. When a woman using the patch, her ability to become pregnant returns quickly. This is a significant factor in the decision to administer tetracycline-derived antibiotics following an abortion when synthetic hormone contraceptives are to be used afterwards. Drugs containing St. Johns Wort are also known to affect the effectiveness of hormonal contraceptives and it has also been found that the Ortho Evra patch is less effective in women over 198 pounds

8.
Pharmacokinetics
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Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as, pharmaceutical drugs, pesticides, food additives, cosmetic ingredients, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, both together influence dosing, benefit, and adverse effects, as seen in PK/PD models. Pharmacokinetic properties of chemicals are affected by the route of administration and these may affect the absorption rate. Models have been developed to simplify conceptualization of the processes that take place in the interaction between an organism and a chemical substance. The various compartments that the model is divided into are commonly referred to as the ADME scheme, absorption - the process of a substance entering the blood circulation. Distribution - the dispersion or dissemination of substances throughout the fluids, metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion - the removal of the substances from the body, in rare cases, some drugs irreversibly accumulate in body tissue. The two phases of metabolism and excretion can also be grouped together under the title elimination, the study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. All these concepts can be represented through mathematical formulas that have a graphical representation. The model outputs for a drug can be used in industry or in the application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals, in practice, it is generally considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph, compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model. The final outcome of the transformations that a drug undergoes in an organism, a number of functional models have been developed in order to simplify the study of pharmacokinetics. These models are based on a consideration of an organism as a number of related compartments, the simplest idea is to think of an organism as only one homogenous compartment. However, these models do not always reflect the real situation within an organism

9.
Bioavailability
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By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes, its bioavailability generally decreases or may vary from patient to patient, Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. Bioavailability is defined differently for drugs as opposed to dietary supplements primarily due to the method of administration and Food. Bioaccessibility is a related to bioavailability in the context of biodegradation. A molecule is said to be bioaccessible when is available to cross a cellular membrane from the environment. In pharmacology, bioavailability is a measurement of the rate and extent to which a drug reaches at the site of action and it is denoted by the letter f. Therefore, bioavailability for dietary supplements can be defined as the proportion of the administered substance capable of being absorbed, in both pharmacology and nutrition sciences, bioavailability is measured by calculating the area under curve of the drug concentration time profile. Bioavailability is commonly a factor in the production of crops. Toxic materials in soil, such as lead from paint may be rendered unavailable to animals ingesting contaminated soil by supplying phosphorus fertilizers in excess and it is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The comparison must be normalized, consequently, the amount absorbed is corrected by dividing the corresponding dose administered. The absolute bioavailability is the area under curve non-intravenous divided by AUC intravenous. For example, the formula for calculating F for a drug administered by the route is given below. If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability, although knowing the true extent of systemic absorption is clearly useful, in practice it is not determined as frequently as one may think. The reason for this is that its assessment requires a reference, that is. These limitations may be overcome, however, by administering a low dose of an isotopically labelled drug concomitantly with a therapeutic non-labelled oral dose. This technique eliminates pharmacokinetic issues on non-equivalent clearance as well as enabling the intravenous dose to be administered with a minimum of toxicology, the technique was first applied using stable-isotopes such as 13C and mass-spectrometry to distinguish the isotopes by mass difference. More recently, 14C labelled drugs are administered intravenously and accelerator mass spectrometry used to measure the isotopically labelled drug along with mass spectrometry for the unlabelled drug, in all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously. Intravenous administration of a drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution

10.
Human serum albumin
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Human serum albumin is the serum albumin found in human blood. It is the most abundant protein in blood plasma, it constitutes about half of serum protein. It is produced in the liver, albumin transports hormones, fatty acids, and other compounds, buffers pH, and maintains oncotic pressure, among other functions. Albumin is synthesized in the liver as preproalbumin, which has an N-terminal peptide that is removed before the nascent protein is released from the endoplasmic reticulum. The product, proalbumin, is in turn cleaved in the Golgi vesicles to produce the secreted albumin, the reference range for albumin concentrations in serum is approximately 35 -50 g/L. It has a serum half-life of approximately 20 days and it has a molecular mass of 66.5 kDa. The gene for albumin is located on chromosome 4 and mutations in this gene can result in anomalous proteins, the human albumin gene is 16,961 nucleotides long from the putative cap site to the first poly addition site. It is split into 15 exons that are placed within the 3 domains thought to have arisen by triplication of a single primordial domain. Serum albumin concentration is typically 35 -50 g/L Hypoalbuminemia is a low blood albumin levels, typically, this condition is due to abrupt dehydration. Chronic dehydration needs to be treated with zinc as well as with water, zinc reduces cell swelling caused by decreased intake of water and also increases retention of salt. In the dehydrated state, the body has too high an osmolarity and, it appears, zinc also regulates transport of the cellular osmolyte taurine, and albumin is known to increase cellular taurine absorption. Zinc has been shown to increase production from beta-carotene. It is possible that a retinol deficiency alone could cause albumin levels to become raised, patients recovering from chronic dehydration may develop dry eyes as the body uses up its vitamin A store. Retinol causes cells to swell with water, hyperalbuminemia is also associated with high protein diets. Human albumin solution or HSA is available for use, usually at concentrations of 5-25%. Human albumin is used to replace lost fluid and help restore blood volume in trauma, burns. A Cochrane systematic review of 37 trials found no evidence that albumin, compared with alternatives such as saline. Human serum albumin has been used as a component of a frailty index and this reaction can be inhibited in the presence of antioxidant agents

11.
Drug metabolism
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Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. These pathways are a form of biotransformation present in all groups of organisms. These reactions often act to detoxify poisonous compounds, the study of drug metabolism is called pharmacokinetics. The metabolism of drugs is an important aspect of pharmacology. For example, the rate of metabolism determines the duration and intensity of a drugs pharmacologic action, the enzymes of xenobiotic metabolism, particularly the glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides. Drug metabolism is divided into three phases, in phase I, enzymes such as cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics. These modified compounds are conjugated to polar compounds in phase II reactions. These reactions are catalysed by enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be processed, before being recognised by efflux transporters. Drug metabolism often converts lipophilic compounds into hydrophilic products that are readily excreted. The exact compounds an organism is exposed to will be unpredictable, and may differ widely over time. The solution that has evolved to address this problem is an elegant combination of physical barriers, all organisms use cell membranes as hydrophobic permeability barriers to control access to their internal environment. This selective uptake means that most hydrophilic molecules cannot enter cells, in contrast, the diffusion of hydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid-soluble xenobiotics using membrane barriers. However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics and these systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general one or more charged groups. However, since these compounds are few in number, specific enzymes can recognize, the metabolism of xenobiotics is often divided into three phases, - modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells, in phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the cytochrome P-450-dependent mixed-function oxidase system and these enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates

12.
CYP3A4
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Cytochrome P450 3A4, is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules, such as toxins or drugs, while many drugs are deactivated by CYP3A4, there are also some drugs which are activated by the enzyme. Some substances, such as juice and some drugs, interfere with the action of CYP3A4. These substances will therefore either amplify or weaken the action of drugs that are modified by CYP3A4. CYP3A4 is a member of the cytochrome P450 family of oxidizing enzymes, several other members of this family are also involved in drug metabolism, but CYP3A4 is the most common and the most versatile one. Like all members of family, it is a hemoprotein. In humans, the CYP3A4 protein is encoded by the CYP3A4 gene and this gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. CYP3A4 is a member of the cytochrome P450 superfamily of enzymes, the cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids components. The CYP3A4 protein localizes to the endoplasmic reticulum, and its expression is induced by glucocorticoids and this enzyme is involved in the metabolism of approximately half the drugs that are used today, including acetaminophen, codeine, ciclosporin, diazepam, and erythromycin. The enzyme also metabolizes some steroids and carcinogens, most drugs undergo deactivation by CYP3A4, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYP3A4 to form their active compounds, CYP3A4 also possesses epoxygenase activity in that it metabolizes arachidonic acid to epoxyeicosatrienoic acids, i. e. -8, 9-, -11, 12-, and -14, 15-epoxyeicosatrienoic acids. The EETs have a range of activities including the promotion of certain types of cancers. 20-HETE has a range of activities that also include growth stimulation in breast. The CYP3A4 gene exhibits a more complicated upstream regulatory region in comparison with its paralogs. This increased complexity renders the CYP3A4 gene more sensitive to endogenous and exogenous PXR and CAR ligands and this change in consequence contributes to an increased human defense against cholestasis. Fetuses do not really express CYP3A4 in their liver tissue, but rather CYP3A7, CYP3A4 is absent in fetal liver but increases to approximately 40% of adult levels in the fourth month of life and 72% at 12 months. Although CYP3A4 is predominantly found in the liver, it is present in other organs and tissues of the body. CYP3A4 in the plays a important role in the metabolism of certain drugs

13.
Excretion
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Excretion is the process by which metabolic wastes and other non-useful materials are eliminated from an organism. In vertebrates this is carried out by the lungs, kidneys. This is in contrast with secretion, where the substance may have specific tasks after leaving the cell, excretion is an essential process in all forms of life. For example, in urine is expelled through the urethra. In unicellular organisms, waste products are discharged directly through the surface of the cell, green plants produce carbon dioxide and water as respiratory products. In green plants, the carbon dioxide released during respiration gets utilized during photosynthesis, oxygen is a by product generated during photosynthesis, and exits through stomata, root cell walls, and other routes. Plants can get rid of water by transpiration and guttation. These latter processes do not need added energy, they act passively, however, during the pre-abscission phase, the metabolic levels of a leaf are high. Plants also excrete some waste substances into the soil around them, in animals, the main excretory products are carbon dioxide, ammonia, urea, uric acid, guanine and creatine. The liver and kidneys clear many substances from the blood, aquatic animals usually excrete ammonia directly into the external environment, as this compound has high solubility and there is ample water available for dilution. In terrestrial animals ammonia-like compounds are converted into other materials as there is less water in the environment. Birds excrete their nitrogenous wastes as uric acid in the form of a paste and this is metabolically more expensive, but allows more efficient water retention and it can be stored more easily in the egg. Many avian species, especially seabirds, can also excrete salt via specialized nasal salt glands, in insects, a system involving Malpighian tubules is utilized to excrete metabolic waste. Metabolic waste diffuses or is actively transported into the tubule, which transports the wastes to the intestines, the metabolic waste is then released from the body along with fecal matter. The excreted material may be called dejecta or ejecta, in pathology the word ejecta is more commonly used. UAlberta. ca, Animation of excretion Brian J Ford on leaf fall in Nature

14.
Feces
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Feces or faeces are the solid or semisolid metabolic waste from an animals digestive tract, discharged through the anus or cloaca during a process called defecation. Urine and feces together are called excreta, collected feces has various uses, namely as fertilizer or soil conditioner in agriculture, as a fuel source, or for medicinal purposes. After an animal has digested eaten material, the remains of material are discharged from its body as waste. Although it is lower in energy than the food from which it is derived, feces may retain a large amount of energy and this means that of all food eaten, a significant amount of energy remains for the decomposers of ecosystems. Many organisms feed on feces, from bacteria to fungi to insects such as dung beetles, some may specialize in feces, while others may eat other foods as well. Feces serve not only as a food, but also as a supplement to the usual diet of some animals. Feces and urine, which reflect light, are important to raptors such as kestrels. Seeds also may be found in feces, animals who eat fruit are known as frugivores. An advantage for a plant in having fruit is that animals will eat the fruit and this mode of seed dispersal is highly successful, as seeds dispersed around the base of a plant are unlikely to succeed and often are subject to heavy predation. Provided the seed can withstand the pathway through the system, it is not only likely to be far away from the parent plant. This cycling of matter is known as the biogeochemical cycle, the distinctive odor of feces is due to bacterial action. Gut flora produce compounds such as indole, skatole, and thiols and these are the same compounds that are responsible for the odor of flatulence. Consumption of foods prepared with spices may result in the spices being undigested, the perceived bad odor of feces has been hypothesized to be a deterrent for humans, as consuming or touching it may result in sickness or infection. Human perception of the odor may be contrasted by an animals perception of it, for example. In humans and depending on the individual and the circumstances, defecation may occur daily, extensive hardening of the feces may cause prolonged interruption in the routine and is called constipation. Human fecal matter varies significantly in appearance, depending on diet, normally it is semisolid, with a mucus coating. The brown coloration comes from a combination of bile and bilirubin, in newborn babies, initially fecal matter is yellow-green after the meconium. This coloration comes from the presence of bile alone, throughout the life of an ordinary human, one may experience many types of feces

15.
Urine
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Urine is a liquid by-product of metabolism in the bodies of many animals, including humans. It is expelled from the kidneys and flows through the ureters to the urinary bladder, cellular metabolism generates numerous by-products, many nitrogenous, that require clearance from the bloodstream. These by-products are eventually expelled from the body during urination, the method for excreting water-soluble chemicals from the body. These chemicals can be detected and analyzed by urinalysis, of the many such substances that exist, the three main nitrogenous wastes of the mammalian body are urea, uric acid, and creatinine. Animal urine forms part of the nitrogen cycle, in balanced ecosystems it fertilizes soil and plants, which in turn continue to support the animal population. Some animals use it to mark their territories, human urine and human feces are collectively referred to as human waste, as sewage, they require sewage treatment in places where population density is high. Livestock urine and feces similarly require proper management if the population density is high. Such management is part of ecological sanitation, most animals have excretory systems for elimination of soluble toxic wastes. In humans, soluble wastes are excreted primarily by the system and, to a lesser extent in terms of urea. The urinary system consists of the kidneys, ureters, urinary bladder, the system produces urine by a process of filtration, reabsorption, and tubular secretion. The kidneys extract the soluble wastes from the bloodstream, as well as water, sugars. The resulting urine contains high concentrations of urea and other substances, urine flows from the kidney through the ureter, bladder, and finally the urethra before passing from the body. Research looking at the duration of urination in a range of species found that 9 larger species urinated for 21 ±13 seconds irrespective of body size. Smaller species including rodents and bats cannot produce jets and instead urinate with a series of drops, producing too much or too little urine needs medical attention. Polyuria is a condition of excessive production of urine, oliguria when <400 mL are produced, about 91-96% of urine consists of water. Urine also contains an assortment of inorganic salts and organic compounds, including proteins, hormones, the total solids in urine are on average 59 g per person per day. Organic matter makes up between 65% and 85% of urine dry solids, with volatile solids comprising 75–85% of total solids, urea is the largest constituent of the solids, constituting more than 50% of the total. On an elemental level, human urine contains 6.87 g/L carbon,8.12 g/L nitrogen,8.25 g/L oxygen, the exact proportions vary with individuals and with factors such as diet and health

16.
PubChem
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PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information, a component of the National Library of Medicine, PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be downloaded via FTP. PubChem contains substance descriptions and small molecules with fewer than 1000 atoms and 1000 bonds, more than 80 database vendors contribute to the growing PubChem database. PubChem consists of three dynamically growing primary databases, as of 28 January 2016, Compounds,82.6 million entries, contains pure and characterized chemical compounds. Substances,198 million entries, contains also mixtures, extracts, complexes, bioAssay, bioactivity results from 1.1 million high-throughput screening programs with several million values. PubChem contains its own online molecule editor with SMILES/SMARTS and InChI support that allows the import and export of all common chemical file formats to search for structures and fragments. In the text search form the database fields can be searched by adding the name in square brackets to the search term. A numeric range is represented by two separated by a colon. The search terms and field names are case-insensitive, parentheses and the logical operators AND, OR, and NOT can be used. AND is assumed if no operator is used, example,0,5000,50,10 -5,5 PubChem was released in 2004. The American Chemical Society has raised concerns about the publicly supported PubChem database and they have a strong interest in the issue since the Chemical Abstracts Service generates a large percentage of the societys revenue. To advocate their position against the PubChem database, ACS has actively lobbied the US Congress, soon after PubChems creation, the American Chemical Society lobbied U. S. Congress to restrict the operation of PubChem, which they asserted competes with their Chemical Abstracts Service

17.
Guide to Pharmacology
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The IUPHAR/BPS Guide to PHARMACOLOGY is an open-access website, acting as a portal to information on the biological targets of licensed drugs and other small molecules. The Guide to PHARMACOLOGY is developed as a joint venture between the International Union of Basic and Clinical Pharmacology and the British Pharmacological Society and this replaces and expands upon the original 2009 IUPHAR Database. The information featured includes pharmacological data, target and gene nomenclature, overviews and commentaries on each target family are included, with links to key references. The Guide to PHARMACOLOGY was initially made available online in December 2011 with additional material released in July 2012 and its network of over 700 specialist advisors contribute expertise and data. The current PI and Grant holder of the GtoPdb project is Prof. Jamie A. Davies, the development and release of the first version of the GtoPdb in 2012 was described in an editorial published in the British Journal of Pharmacology entitled Guide to Pharmacology. org- an update. The IUPHAR-DB is no longer being developed and all the contained within this site is now available through the Guide to PHARMACOLOGY. A complete list of all the approved drugs included on the website is available via the ligand list. The Guide to PHARMACOLOGY is being expanded to include information on targets and ligands. Search features on the website include quick and advanced search options, other features include Hot topic news items and a recent receptor-ligand pairing list. A hard copy summary of the database is published as The Concise Guide to Pharmacology 2015/2016 as a series of papers as a bi-annual supplement to the British Journal of Pharmacology. The Guide to PHARMACOLOGY includes links to other relevant resources via target, many of these resources maintain reciprocal links with the relevant Guide to PHARMACOLOGY pages. As of November 2015 the Wellcome Trust is supporting a new project to develop the Guide to Immumopharmacology, the latter continues to be supported by the British Pharmacological Society

18.
DrugBank
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The DrugBank database is a comprehensive, freely accessible, online database containing information on drugs and drug targets. As both a bioinformatics and a resource, DrugBank combines detailed drug data with comprehensive drug target information. Because of its scope, comprehensive referencing and unusually detailed data descriptions. As a result, links to DrugBank are maintained for nearly all drugs listed in Wikipedia, DrugBank is widely used by the drug industry, medicinal chemists, pharmacists, physicians, students and the general public. Its extensive drug and drug-target data has enabled the discovery and repurposing of a number of existing drugs to treat rare, the latest release of the database contains 8227 drug entries including 2003 FDA-approved small molecule drugs,221 FDA-approved biotech drugs,93 nutraceuticals and over 6000 experimental drugs. Additionally,4270 non-redundant protein sequences are linked to these drug entries, each DrugCard entry contains more than 200 data fields with half of the information being devoted to drug/chemical data and the other half devoted to drug target or protein data. Four additional databases, HMDB, T3DB, SMPDB and FooDB are also part of a suite of metabolomic/cheminformatic databases. The first version of DrugBank was released in 2006 and this early release contained relatively modest information about 841 FDA-approved small molecule drugs and 113 biotech drugs. It also included information on 2133 drug targets, the second version of DrugBank was released in 2009. This greatly expanded and improved version of the database included 1344 approved small molecule drugs and 123 biotech drugs as well as 3037 unique drug targets. Version 2.0 also included, for the first time, withdrawn drugs and illicit drugs, version 3.0 was released in 2011. This version contained 1424 approved small molecule drugs and 132 biotech drugs as well as >4000 unique drug targets, version 3.0 also included drug transporter data, drug pathway data, drug pricing, patent and manufacturing data as well as data on >5000 experimental drugs. Version 4.0 was released in 2014 and this version included 1558 FDA-approved small molecule drugs,155 biotech drugs and 4200 unique drug targets. Version 4.0 also incorporated information on drug metabolites, drug taxonomy, drug spectra, drug binding constants. Table 1 provides a complete statistical summary of the history of DrugBank’s development. All data in DrugBank is non-proprietary or is derived from a non-proprietary source and it is freely accessible and available to anyone. In addition, nearly every item is fully traceable and explicitly referenced to the original source. DrugBank data is available through a web interface and downloads

19.
ChemSpider
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ChemSpider is a database of chemicals. ChemSpider is owned by the Royal Society of Chemistry, the database contains information on more than 50 million molecules from over 500 data sources including, Each chemical is given a unique identifier, which forms part of a corresponding URL. This is an approach to develop an online chemistry database. The search can be used to widen or restrict already found results, structure searching on mobile devices can be done using free apps for iOS and for the Android. The ChemSpider database has been used in combination with text mining as the basis of document markup. The result is a system between chemistry documents and information look-up via ChemSpider into over 150 data sources. ChemSpider was acquired by the Royal Society of Chemistry in May,2009, prior to the acquisition by RSC, ChemSpider was controlled by a private corporation, ChemZoo Inc. The system was first launched in March 2007 in a release form. ChemSpider has expanded the generic support of a database to include support of the Wikipedia chemical structure collection via their WiChempedia implementation. A number of services are available online. SyntheticPages is an interactive database of synthetic chemistry procedures operated by the Royal Society of Chemistry. Users submit synthetic procedures which they have conducted themselves for publication on the site and these procedures may be original works, but they are more often based on literature reactions. Citations to the published procedure are made where appropriate. They are checked by an editor before posting. The pages do not undergo formal peer-review like a journal article. The comments are moderated by scientific editors. The intention is to collect practical experience of how to conduct useful chemical synthesis in the lab, while experimental methods published in an ordinary academic journal are listed formally and concisely, the procedures in ChemSpider SyntheticPages are given with more practical detail. Comments by submitters are included as well, other publications with comparable amounts of detail include Organic Syntheses and Inorganic Syntheses

20.
ChEMBL
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ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug-like properties. It is maintained by the European Bioinformatics Institute, of the European Molecular Biology Laboratory, based at the Wellcome Trust Genome Campus, Hinxton, the database, originally known as StARlite, was developed by a biotechnology company called Inpharmatica Ltd. later acquired by Galapagos NV. The data was acquired for EMBL in 2008 with an award from The Wellcome Trust, resulting in the creation of the ChEMBL chemogenomics group at EMBL-EBI, the ChEMBL database contains compound bioactivity data against drug targets. Bioactivity is reported in Ki, Kd, IC50, and EC50, data can be filtered and analyzed to develop compound screening libraries for lead identification during drug discovery. ChEMBL version 2 was launched in January 2010, including 2.4 million bioassay measurements covering 622,824 compounds and this was obtained from curating over 34,000 publications across twelve medicinal chemistry journals. ChEMBLs coverage of available bioactivity data has grown to become the most comprehensive ever seen in a public database, in October 2010 ChEMBL version 8 was launched, with over 2.97 million bioassay measurements covering 636,269 compounds. ChEMBL_10 saw the addition of the PubChem confirmatory assays, in order to integrate data that is comparable to the type, ChEMBLdb can be accessed via a web interface or downloaded by File Transfer Protocol. It is formatted in a manner amenable to computerized data mining, ChEMBL is also integrated into other large-scale chemistry resources, including PubChem and the ChemSpider system of the Royal Society of Chemistry. In addition to the database, the ChEMBL group have developed tools and these include Kinase SARfari, an integrated chemogenomics workbench focussed on kinases. The system incorporates and links sequence, structure, compounds and screening data, the primary purpose of ChEMBL-NTD is to provide a freely accessible and permanent archive and distribution centre for deposited data. July 2012 saw the release of a new data service, sponsored by the Medicines for Malaria Venture. The data in this service includes compounds from the Malaria Box screening set, myChEMBL, the ChEMBL virtual machine, was released in October 2013 to allow users to access a complete and free, easy-to-install cheminformatics infrastructure. In December 2013, the operations of the SureChem patent informatics database were transferred to EMBL-EBI, in a portmanteau, SureChem was renamed SureChEMBL. 2014 saw the introduction of the new resource ADME SARfari - a tool for predicting and comparing cross-species ADME targets

21.
European Chemicals Agency
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ECHA is the driving force among regulatory authorities in implementing the EUs chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and it is located in Helsinki, Finland. The Agency, headed by Executive Director Geert Dancet, started working on 1 June 2007, the REACH Regulation requires companies to provide information on the hazards, risks and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most commonly used substances have been registered, the information is technical but gives detail on the impact of each chemical on people and the environment. This also gives European consumers the right to ask whether the goods they buy contain dangerous substances. The Classification, Labelling and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU. This worldwide system makes it easier for workers and consumers to know the effects of chemicals, companies need to notify ECHA of the classification and labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100000 substances, the information is freely available on their website. Consumers can check chemicals in the products they use, Biocidal products include, for example, insect repellents and disinfectants used in hospitals. The Biocidal Products Regulation ensures that there is information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation, the law on Prior Informed Consent sets guidelines for the export and import of hazardous chemicals. Through this mechanism, countries due to hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have effects on human health and the environment are identified as Substances of Very High Concern 1. These are mainly substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment, other substances considered as SVHCs include, for example, endocrine disrupting chemicals. Companies manufacturing or importing articles containing these substances in a concentration above 0 and they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy, once a substance has been officially identified in the EU as being of very high concern, it will be added to a list. This list is available on ECHA’s website and shows consumers and industry which chemicals are identified as SVHCs, Substances placed on the Candidate List can then move to another list

22.
Chemical formula
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These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, the simplest types of chemical formulas are called empirical formulas, which use letters and numbers indicating the numerical proportions of atoms of each type. Molecular formulas indicate the numbers of each type of atom in a molecule. For example, the formula for glucose is CH2O, while its molecular formula is C6H12O6. This is possible if the relevant bonding is easy to show in one dimension, an example is the condensed molecular/chemical formula for ethanol, which is CH3-CH2-OH or CH3CH2OH. For reasons of structural complexity, there is no condensed chemical formula that specifies glucose, chemical formulas may be used in chemical equations to describe chemical reactions and other chemical transformations, such as the dissolving of ionic compounds into solution. A chemical formula identifies each constituent element by its chemical symbol, in empirical formulas, these proportions begin with a key element and then assign numbers of atoms of the other elements in the compound, as ratios to the key element. For molecular compounds, these numbers can all be expressed as whole numbers. For example, the formula of ethanol may be written C2H6O because the molecules of ethanol all contain two carbon atoms, six hydrogen atoms, and one oxygen atom. Some types of compounds, however, cannot be written with entirely whole-number empirical formulas. An example is boron carbide, whose formula of CBn is a variable non-whole number ratio with n ranging from over 4 to more than 6.5. When the chemical compound of the consists of simple molecules. These types of formulas are known as molecular formulas and condensed formulas. A molecular formula enumerates the number of atoms to reflect those in the molecule, so that the formula for glucose is C6H12O6 rather than the glucose empirical formula. However, except for very simple substances, molecular chemical formulas lack needed structural information, for simple molecules, a condensed formula is a type of chemical formula that may fully imply a correct structural formula. For example, ethanol may be represented by the chemical formula CH3CH2OH

23.
Jmol
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Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool and it is written in the programming language Java, so it can run on the operating systems Windows, macOS, Linux, and Unix, if Java is installed. It is free and open-source software released under a GNU Lesser General Public License version 2.0, a standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways, for example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile. There is also a JavaScript-only version, JSmol, that can be used on computers with no Java, the Jmol applet, among other abilities, offers an alternative to the Chime plug-in, which is no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS9. Jmol requires Java installation and operates on a variety of platforms. For example, Jmol is fully functional in Mozilla Firefox, Internet Explorer, Opera, Google Chrome, fast and Scriptable Molecular Graphics in Web Browsers without Java3D

24.
Simplified molecular-input line-entry system
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The simplified molecular-input line-entry system is a specification in form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules, the original SMILES specification was initiated in the 1980s. It has since modified and extended. In 2007, a standard called OpenSMILES was developed in the open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. The Environmental Protection Agency funded the project to develop SMILES. It has since modified and extended by others, most notably by Daylight Chemical Information Systems. In 2007, a standard called OpenSMILES was developed by the Blue Obelisk open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, in July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being slightly more human-readable than InChI, the term SMILES refers to a line notation for encoding molecular structures and specific instances should strictly be called SMILES strings. However, the term SMILES is also used to refer to both a single SMILES string and a number of SMILES strings, the exact meaning is usually apparent from the context. The terms canonical and isomeric can lead to confusion when applied to SMILES. The terms describe different attributes of SMILES strings and are not mutually exclusive, typically, a number of equally valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol, algorithms have been developed to generate the same SMILES string for a given molecule, of the many possible strings, these algorithms choose only one of them. This SMILES is unique for each structure, although dependent on the algorithm used to generate it. These algorithms first convert the SMILES to a representation of the molecular structure. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database, there is currently no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, and these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES

25.
International Chemical Identifier
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Initially developed by IUPAC and NIST from 2000 to 2005, the format and algorithms are non-proprietary. The continuing development of the standard has supported since 2010 by the not-for-profit InChI Trust. The current version is 1.04 and was released in September 2011, prior to 1.04, the software was freely available under the open source LGPL license, but it now uses a custom license called IUPAC-InChI Trust License. Not all layers have to be provided, for instance, the layer can be omitted if that type of information is not relevant to the particular application. InChIs can thus be seen as akin to a general and extremely formalized version of IUPAC names and they can express more information than the simpler SMILES notation and differ in that every structure has a unique InChI string, which is important in database applications. Information about the 3-dimensional coordinates of atoms is not represented in InChI, the InChI algorithm converts input structural information into a unique InChI identifier in a three-step process, normalization, canonicalization, and serialization. The InChIKey, sometimes referred to as a hashed InChI, is a fixed length condensed digital representation of the InChI that is not human-understandable. The InChIKey specification was released in September 2007 in order to facilitate web searches for chemical compounds and it should be noted that, unlike the InChI, the InChIKey is not unique, though collisions can be calculated to be very rare, they happen. In January 2009 the final 1.02 version of the InChI software was released and this provided a means to generate so called standard InChI, which does not allow for user selectable options in dealing with the stereochemistry and tautomeric layers of the InChI string. The standard InChIKey is then the hashed version of the standard InChI string, the standard InChI will simplify comparison of InChI strings and keys generated by different groups, and subsequently accessed via diverse sources such as databases and web resources. Every InChI starts with the string InChI= followed by the version number and this is followed by the letter S for standard InChIs. The remaining information is structured as a sequence of layers and sub-layers, the layers and sub-layers are separated by the delimiter / and start with a characteristic prefix letter. The six layers with important sublayers are, Main layer Chemical formula and this is the only sublayer that must occur in every InChI. The atoms in the formula are numbered in sequence, this sublayer describes which atoms are connected by bonds to which other ones. Describes how many hydrogen atoms are connected to each of the other atoms, the condensed,27 character standard InChIKey is a hashed version of the full standard InChI, designed to allow for easy web searches of chemical compounds. Most chemical structures on the Web up to 2007 have been represented as GIF files, the full InChI turned out to be too lengthy for easy searching, and therefore the InChIKey was developed. With all databases currently having below 50 million structures, such duplication appears unlikely at present, a recent study more extensively studies the collision rate finding that the experimental collision rate is in agreement with the theoretical expectations. Example, Morphine has the structure shown on the right, as the InChI cannot be reconstructed from the InChIKey, an InChIKey always needs to be linked to the original InChI to get back to the original structure

Graph that demonstrates the Michaelis–Menten kinetics model for the relationship between an enzyme and a substrate: one of the parameters studies in pharmacokinetics, where the substrate is a pharmaceutical drug.

Different forms of tablets, which will have different pharmacokinetic behaviours after their administration.

The time course of drug plasma concentrations over 96 hours following oral administrations every 24 hours. Note that the AUC in steady state equals AUC∞ after the first dose.